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3D Fragment Library Consortium

Summary

The 3D Fragment Consortium brings together UK-based not-for-profit drug discovery institutes and academic groups, working in partnership to build a collection of a chemically diverse molecules with a particular focus on fragments that incorporate 3D structure. The consortium is looking to collaborate with other research groups to expand the collection and make it available for screening against new biological targets to help kick-start hit discovery programmes and provide a foundation for a vibrant pre-competitive drug discovery network across the UK.

Background

Fragment screening using biophysical screening techniques is a proven method to identify validated hits that can subsequently be developed into therapeutic agents. As a result of their size (MW typically <250Da) and through careful selection, fragments provide the opportunity to sample chemical space more effectively than other screening methods, such as conventional HTS. Highly ligand efficient hits have routinely been identified for a range of soluble protein targets such as kinases, GPCRs, proteases and NHRs as well as for less tractable targets such as protein-protein interactions (PPIs). Whilst broad diversity is essential to maximise chances of success, recent analyses of the shape characteristics of library compounds reveal an over-reliance on flat sp2-rich aromatic systems. Enrichment of collections with compounds possessing a greater degree of 3D shape will increase overall library diversity and is expected to lead to improved tractability and hit follow-up options for a wider selection of target classes.

What the 3D Fragment Consortium will offer

The consortium has built bespoke computational tools to analyse chemical space and is currently using this to establish a core library of diverse 3D fragments. The team is keen to share this information with collaborators to highlight key areas of chemistry space that are currently under-represented and to identify novel synthetic chemistry ideas that could help to populate these high value regions of the library.

For those ideas that are adopted, the resulting fragments will be screened against >40 targets/year across a range of disease areas. Not only will this deliver a richer data source to help develop the library further but it will provide a clear opportunity for synthetic chemistry groups to demonstrate the impact of their research in a drug discovery setting. All structures and associated biological test data will be considered to be pre-competitive and will be shared with those who contribute compounds to the collection. This, it is hoped, will promote new collaboration opportunities between these groups and foster a greater degree of knowledge sharing across the broader drug discovery research community.

How to get involved

Pharma and biotechs: opportunities help to shape the collection to meet your specific needs